Components of signaling pathways that promote proliferation are likely to play a central role in normal cellular growth and differentiation, and are therefore potential targets during pathogenesis, especially neoplastic growth. Guanine nucleotide binding (G) proteins are membrane-associated heterotrimers (alpha, beta, and gamma subunits) and play an important role in transmembrane signal transduction. One type of alpha subunit, Gs, is ADP-ribosylated by cholera toxin and mediates activation of adenylate cyclase. Two point mutations, found at the cholera toxin ribosylation site and a proposed conformational switching area (S-box), have been proposed to be oncogenic in a subset of growth hormone-producing pituitary adenomas. We have carried out G-specific PCR amplification and subsequent cloning of amplified cDNAs from normal human brain tissue, placenta, an SV40-transformed human astroglial cell line, a glioblastoma cell line, (HS683) a primary glioblastoma, and an ACTH-producing pituitary adenoma. Characterization of the recombinant clones showed the presence of novel truncated Gs transcripts in the transformed astroglial cell line SVG, glioblastoma cell line HS683, and glial and corticotroph tumors. Our results suggest that aberrant splicing of Gs may have a modulatory function in transformation.